Safety of radiotherapy for second primary malignancies in patients with chronic lymphocytic leukemia receiving concurrent novel agent treatment
Authors: Samuel R. Kosydar, Sameer A. Parikh, Scott C. Lester, Kari G. Rabe, Wei Ding, Jessica F. Burlile, Saad S. Kenderian, Yucai Wang, Eli Muchtar, Amber B. Koehler, Susan M. Schwager, Susan L. Slager, Neil E. Kay, Timothy G. Call, William G. Breen, Paul J. Hampel
Journal: American Journal of Hematology (2023)

Patients with chronic lymphocytic leukemia (CLL) are at increased risk of developing non-hematologic malignancies.1 Definitive or adjuvant radiation therapy is often a critical component of management for localized solid organ cancers. With the advent of novel agents for CLL, such as bruton tyrosine kinase inhibitors (BTKi) and the BCL-2 inhibitor venetoclax, patients with CLL often receive continuous daily therapy. Prior studies have reported disease flare2 and inferior outcomes among patients where BTKi therapy was interrupted, regardless of the reason for the hold.3 On the other hand, worse outcomes are reported in patients with melanoma receiving concurrent radiotherapy and BRAF inhibitors.4 Platelet dysfunction associated with BTKi also raises concerns for increased bleeding and/or synergy with radiation-induced thrombocytopenia. Safety data to guide the concurrent administration of radiation therapy for a second cancer in patients receiving ongoing CLL novel agent treatment are lacking. Increased toxicity from either component could potentially result in suboptimal delivery of curative intent radiotherapy and substantially impact patient outcomes. The aim of this study was to assess the adverse event profile of concurrent radiation treatment of second primary malignancies in patients receiving novel agent treatment for CLL. This retrospective study included patients with CLL treated at Mayo Clinic from 2014 to 2022. Patients treated with BTKi or venetoclax who concurrently received radiation therapy for a solid organ malignancy were included. Patients who received sequential therapy were excluded. Adverse events, within 3 months of completion of radiotherapy, were described using the Common Terminology Criteria for Adverse Events (CTCAE) version 5. In addition, the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria for hematological adverse events (based on changes from baseline) was also used. SPSS was employed for data analysis (IBM SPSS Statistics for Windows, Version 28.0. Armonk, NY: IBM Corp). Wilcoxon signed-rank test was used to assess the median difference before and after radiation. The Institutional Review Board at Mayo Clinic approved this study. Twenty-six patients were included in the study (Supplemental Table S1). Most patients were male (n = 24, 92.3%) and the median age at start of concurrent radiation treatment was 68 years (range: 51–85). Concurrent CLL-directed treatment consisted of ibrutinib (n = 23), acalabrutinib (n = 2), and venetoclax (n = 1) (Table S2). Four (16%) patients had del (17p) and 18 (82%) patients had unmutated immunoglobulin heavy chain (IGHV) genes. The median number of prior CLL therapies was 1 (range: 0–4) and 20 patients had received prior chemoimmunotherapy. Novel agent dosing prior to starting radiotherapy is shown in Table S2; 58% of patients were receiving a reduced dose. No patients had dose reduction due to anticipation of radiotherapy. The most common second primary malignancies were prostate (n = 9), head/neck (n = 8), non-small cell lung cancer (n = 3); and 1 case each of glioblastoma, invasive ductal carcinoma of the breast, plasmacytoma, melanoma, renal cell carcinoma, and thymoma. The most common conventionally fractionated prescriptions (cGy/fx) were 6000/30 (n = 6) and >6000–7020/20–33 (n = 7). Stereotactic body radiotherapy ranged from 3300/5 to 5400/3 (n = 8). Five patients received other, varied radiotherapy prescriptions (Table S3). Median follow-up time after radiotherapy completion was 1.5 years. Median hemoglobin pre- and post-radiation were 13.3 and 12.4 g/dL, respectively. Per CTCAE criteria, two cases of grade 3 anemia were identified. At baseline, both of these patients had grade 1 anemia. There were no cases of grade 3 or 4 anemia using iwCLL criteria. Median platelet count before radiation was 175.5 × 109/L and after treatment was 140.5 × 109/L. There was one case each of grade 3 and grade 4 thrombocytopenia per CTCAE (Patient 2 and 1 below). Prior to radiation, Patient 1 had a baseline grade 1 thrombocytopenia. Using iwCLL criteria there were two cases of grade 4 thrombocytopenia. The median neutrophil count pre and post radiation were 4.4 × 109/L and 3.4 × 109/L, respectively. One case each of grade 3 (Patient 3, baseline grade 1) and grade 4 (Patient 1, baseline grade 1) neutropenia were reported with both CTCAE and iwCLL criteria. (Table 1). Not applicable: 8 (30.8%) Grade 1: 13 (50.0%) Grade 2: 3 (11.5%) Grade 3: 2 (7.7%) Grade 4: 0 Grade 5: 0 Not applicable: 8 (30.8%) Unrelated: 8 (30.8%) Unlikely: 1 (3.8%) Possibly: 7 (26.9%) Probably: 2 (7.7%) Grade 0: 17 (65.4%) Grade 1: 6 (23.1%) Grade 2: 3 (11.5%) Grade 3: 0 Grade 4: 0 Not applicable: 15 (57.7%) Grade 1: 8 (30.8%) Grade 2: 1 (3.8%) Grade 3: 1 (3.8%) Grade 4: 1 (3.8%) Not applicable: 15 (57.7%) Unrelated: 3 (11.5%) Unlikely: 1 (3.8%) Possibly: 5 (19.2%) Probably: 2 (7.7%) Grade 0: 19 (73.1%) Grade 1: 3 (11.5%) Grade 2: 2 (7.7%) Grade 3: 0 Grade 4: 2 (7.7%) Not applicable: 21 (80.8%) Grade 1: 1 (3.8%) Grade 2: 2 (7.7%) Grade 3: 1 (3.8%) Grade 4: 1 (3.8%) Not applicable: 19 (73.1%) Unrelated: 1 (3.8%) Unlikely: 0 Possibly: 4 (15.4%) Probably: 2 (7.7%) Grade 0: 19 (73.1%) Grade 1: 5 (19.2%) Grade 2: 0 Grade 3: 1 (3.8%) Grade 4: 1 (3.8%) Grade 3 or greater non-hematological toxicities occurred in two patients discussed below (Patient 1 and 2, Table 1). Patient 1 was a 58-year-old male with CLL (IGHV unmutated, del (17p), TP53 mutated) and squamous cell carcinoma of the right retromolar trigone. Following surgical resection, he underwent adjuvant chemoradiation of 6000 cGy (30 fractions) with weekly cisplatin while continuing ibrutinib 280 mg daily. Radiation was complicated by grade 3 mucositis. Two weeks after completion of cisplatin, ibrutinib was dose reduced to 140 mg due to worsening pancytopenia. One week later, the patient presented to the ED with new fever and progressively worsening pancytopenia, and was diagnosed with invasive pulmonary aspergillosis and pseudomonas pneumonia. Ibrutinib was subsequently held, but radiation continued to be completed. He developed a worsening lung infection and ultimately enrolled in hospice care. Patient 2 was a 78-year-old male with CLL (trisomy 12) with squamous cell of the left parotid who underwent definitive radiotherapy with 1000 cGy (five fractions) of photon-based radiation followed by 5600 cGy (28 fractions) of proton therapy while on reduced dose ibrutinib (140 mg every 3 days dosing used prior to start of radiotherapy and not further modified). He presented 28 days after completion of radiation with 1 week of shortness of breath and was found to have pseudomonal pneumonia requiring intubation with course complicated by sepsis and acute renal failure. Ibrutinib was held on admission. The patient died with multiorgan failure. Patient 3 was a 66-year-old male with CLL (mutated IGHV, del (11q)) with squamous cell carcinoma of the right temple who was treated with adjuvant photon-based radiotherapy consisting of 6600 cGy (33 fractions) while on ibrutinib 420 mg daily. Prior to radiation, the patient was neutropenic to 1.2 × 109/L that improved to 2.4 × 109/L during course of radiation, without any bone marrow stimulant. Two weeks after completion of radiation, patient developed worsening neutropenia, which nadired at 0.5 × 109/L without fever or other indication for hospitalization. The dose of ibrutinib was reduced to 280 mg daily due to myelosuppression. Overall, three patients experienced at least one grade 3/4 toxicity. All non-hematological adverse events are documented in Table S4. There were no cases of radiation dose modification. There were three cases of ibrutinib dose reduction or discontinuation during radiation (Patients 1–3 as detailed in Table S4) in the context of pancytopenia, critical illness and acute renal failure, and neutropenia, respectively. There were no cases of dose reduction in anticipation of radiation or immediately following completion of radiation course. This is the first study that assessed patients with CLL on novel agents who were concurrently treated with radiotherapy for a solid organ malignancy. Our study found limited treatment related adverse events. Most patients (n = 23) did not experience a severe cytopenia. The statistically significant decreases in median hemoglobin, platelet, and neutrophil counts across the cohort after radiation were not clinically meaningful. We did not find any evidence of grade ≥3 hemorrhage. One case of grade 2 pleural hemorrhage, grade 1 epistaxis, and grade 1 hematuria were observed. There were no events of tumor lysis syndrome, malignant hypertension, or severe cardiac arrhythmias. There was one case of grade 2 atrial flutter in a patient with a history of paroxysmal atrial flutter. Radiation side effects did not appear to be heightened. The most common side effects documented were grade 1 fatigue (n = 7, 26.9%) and grade 1 radiation dermatitis (n = 5, 19.2%). Every patient completed their course of radiation and there were no cases of dose reduction for radiation or delay in treatment. To our knowledge, there are no published data for concurrent novel agents and radiotherapy in the setting of lymphoid malignancies except for a single abstract. Ho et al. included mostly patients with lymphoma (n = 60, 87%) and the indication for radiotherapy was primarily for treatment of lymphoma (85%).5 Increased neutropenia was reported with concurrent ibrutinib and radiotherapy; however, concurrent treatment was defined as receiving the novel agent within 5 days of radiation treatment rather than a true, overlapping administration. Use of small molecule inhibitors with radiation have been explored in other malignancies. BRAF inhibitor vemurafenib with concomitant radiation for melanoma was retrospectively associated with worse survival and increased toxicity compared to interrupted treatment.4 In contrast, retrospective analysis of tyrosine kinase inhibitor cabozantinib with concurrent radiation for metastatic renal cell carcinoma reported few grade 3–4 toxicities.6 Evidence-based guidelines for concurrent therapy are lacking. Our results suggest that concurrent treatment should be a shared decision-making discussion regarding potential harms versus benefits. The risk of CLL flare with BTKi interruption has been well documented2 and there is evidence suggesting worsened progression-free survival when BTKi continuous dosing is compromised.3 A comprehensive clinical evaluation that accounts for the patient's medical comorbidities and personal risk factors should inform the discussion. Our retrospective analysis provides the basis for future prospective studies to better assess the adverse event profile and outcomes of concurrent therapy. This analysis provides important information that may inform treatment decisions for CLL patients with secondary solid organ cancers; however, limitations that are inherent to any retrospective study are present. Additionally, although we were able to assess a variety of CLL patients with a diverse collection of secondary malignancies and radiotherapy plans, the heterogenous nature of the cohort precluded reasonable matching to a control population. In conclusion, lack of prohibitive toxicities suggests that concurrent radiation therapy while continuing novel agent CLL therapy may maintain CLL disease control without compromising management of the solid organ cancer. SRK, PJH, SAP, designed the research, collected, analyzed, and interpreted data, and wrote the manuscript; SCL, WD, JFB, SSK, YW, EM, ABK, NEK, TGC, WGB cared for the patients, interpreted the results, and critically reviewed/revised the manuscript; KGR acquired data and critically reviewed/revised the manuscript; KGR, SMS, SLS analyzed data, conducted statistical analyses, and critically reviewed/revised the manuscript; all authors approved the manuscript in its final format. Sameer A. Parikh: Research funding (institution): Janssen, AstraZeneca, Merck, and Genentech. Honoraria (institution): Pharmacyclics, Merck, AstraZeneca, Janssen, BeiGene, Genentech, Amgen, MingSight Pharmaceuticals, TG Therapeutics, Novalgen Limited, Kite Pharma, and AbbVie. Wei Ding: Consulting or Advisory Role: Alexion Pharmaceuticals (institution), Merck (institution), Octapharma USA (institution), BeiGene. Research Funding: Merk (institution), AstraZeneca (institution), BeiGene (institution), Abbvie (institution), DTRM (institution), Octapharma USA (institution). Saad S. Kenderian: Honoraria: Humanigen (institution). Consulting or Advisory Role: Humanigen (institution). Research Funding: Humanigen (institution). Yucai Wang: Consulting or Advisory Role: Loxo (institution), Incyte (institution), Innocare (institution), TG Therapeutics (institution), Kite, a Gilead company (institution), Lilly (institution), Janssen (institution), BeiGene (institution). Stock and Other Ownership Interests. Company: Merck (recipient: An Immediate Family Member). Honoraria: Kite, a Gilead company (institution). Research Funding: InnoCare (institution), Incyte (institution), Novartis (institution), Genentech (institution), Loxo (institution), MorphoSys (institution), Genmab (institution). Eli Muchtar: Consulting or Advisory Role: Protego Biopharma (recipient: self). Honoraria: Janssen (recipient: self). Neil E. Kay: Consulting or Advisory Role: MorphoSys (institution), Celgene (institution), Agios (institution), CytomX Therapeutics (institution), AstraZeneca (institution), Pharmacyclics (institution), DAVA Pharmaceuticals (institution), Juno Therapeutics (institution), Rigel (institution), Oncotracker (institution), Bristol-Myers Squibb (institution), Abbvie (institution), Targeted Oncology (institution), Acerta Pharma/AstraZeneca (institution), MEI Pharma (institution), Sunesis Pharmaceuticals (institution), TG Therapeutics (institution), Tolero Pharmaceuticals (institution), Janssen Biotech (institution), Genentech/Abbvie (institution), CSL Behring (recipient: self), BeiGene (recipient: self). Research Funding: Pharmacyclics/Janssen (recipient: self), Tolero Pharmaceuticals (recipient: self), Acerta Pharma (recipient: self), MEI Pharma (recipient: self), Celgene (recipient: self), Genentech (recipient: self), Sunesis Pharmaceuticals (recipient: self), Abbvie (recipient: self), TG Therapeutics (recipient: self), Bristol-Myers Squibb (recipient: self). William G. Breen: Consulting or Advisory Role: GE Healthcare (institution). Samuel R. Kosydar, Scott C. Lester, Kari G. Rabe, Jessica F. Burlile, Amber B. Koehler, Susan M. Schwager, Susan L. Slager, Timothy G. Call, Paul J. Hampel declare no conflicts of interest. All patients provided prior authorization for participation. The participants of this study did not give written consent for their data to be shared publicly; due to the sensitive nature of the research, supporting data is not available. Table S1. Basic demographics and disease characteristics. Table S2. Chronic lymphocytic leukemia directed therapy data. Table S3. Radiation therapy, toxicity profile per patient, and dose modification data. Table S4. Number of non-hematologic adverse events per Common Terminology Criteria for Adverse Events. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.